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We investigated the combined effects of alendronate and 1alpha-hydroxyvitamin D3 (1alpha(OH)D3) on the bone mass and strength in aged ovariectomized rats and compared them with those of single treatments. Forty-week-old female rats underwent ovariectomy or sham operation, and after 15 weeks, ovariectomized rats were daily administered vehicle alone, alendronate (0.2 or 1.0 mg/kg,p.o.), 1alpha(OH)D3 (0.02 microg/kg, p.o.), or the combinations of 0.2 or 1.0 mg/kg of alendronate and 1alpha(OH)D3. After 12 weeks, the groups receiving combined treatments had significantly increased bone density and mechanical strength of the 4th lumbar vertebral body and the midfemur compared to the vehicle-treated group, and the effects were almost equal to or slightly less than the addition of those of the respective single treatments. The increase in mechanical strength was proportional to that in bone mineral density, suggesting that the stimulatory effects of these treatments on bone strength are ascribable primarily to those on bone mass. Analyses of histology, computed tomography, and biochemical markers confirmed the strong effect of the combined treatment on trabecular bone in particular, which was associated with increased trabecular number and decreased bone turnover. We propose that the combination of daily alendronate and 1alpha(OH)D3 is clinically promising as a curative treatment of established postmenopausal osteoporosis.

The effect of TEI-6363 (5-[E-4-N, N-dimethylaminophenylmethylene]-4-hydroxy-2-[1-methyl imidazole-2-ilthio]-4-[4-phenylbutyl]-2-cyclopentenone), a chemically synthesized prostaglandin A1 derivative, on cell proliferation and osteoblastic differentiation was investigated concurrently. ROS17/2.8 cells (a rat osteosarcoma-derived cell line) were treated with TEI-6363 at two concentrations, 10-7 and 10-6 M, and viable cells were counted to assess cytotoxic effects and determine the growth curve. After 96 h of treatment, there was no evidence of any effect of TEI-6363 on cell viability at either concentration. However, a clear inhibitory effect on cell proliferation was observed after treatment with 10-6 M TEI-6363 for 24 h or longer. A pulse-treatment experiment showed that TEI-6363 induced the inhibition of proliferating ROS17/2.8 cells 24 h after addition. The inhibition of proliferation was associated with Gl-arrest demonstrated by flow cytometric analysis, and incorporation of [3H]thymidine by ROS17/2.8 cells was decreased. Osteoblastic differentiation (assessed on the basis of increased alkaline phosphatase activity and collagen synthesis) was induced by TEI-6363 treatment at 10-6M following Gl-arrest and inhibition of cell proliferation. These results suggest that TEI-6363 arrested the cell cycle of ROS 17/2.8 cells at the Gl phase and induced osteoblastic differentiation. These results did not appear to be dependent on a marked cytotoxic effect.

Menopausal hot flushes (HFs), which manifest as an increase in skin temperature, most frequently occur after menopause and cease with the passage of time. We designed this study to elucidate the characteristics of the elevation of tail skin temperature (TST) in ovariectomized (OVX) rats, which is relevant to human symptoms of HFs. First, we measured TST and rectal temperature (RT) and investigated the time course of their changes up to 20 wk after ovariectomy. The TST in OVX rats (28.4 ± 0.3°C) was significantly ( P = 0.0035) elevated from 2 to 7 wk after the ovariectomy compared with that in sham-operated (Sham) rats (27.0 ± 0.2°C), whereas the RT in OVX rats was elevated from 8 to 20 wk. We next examined the therapeutic effects of estradiol (E2) on the elevation of the TST by continuous subcutaneous infusion. E2 treatment (1.0 μg/day) completely ( P = 0.0232) inhibited the elevation of the TST (28.4 ± 0.3°C for Sham rats, 29.3 ± 0.3°C for OVX rats, 28.2 ± 0.4°C for OVX + E2 1.0 μg/day rats). These results demonstrated that the elevation of TST in OVX rats was exhibited soon after the estrogen removal and diminished with time and that it was normalized with continuous E2 replacement. These characteristics are similar to the symptoms of menopausal HFs in women.